米彦军 Apatinib (YN968D1) reverses multidrug …：米彦军阿帕替尼（yn968d1）逆转多药耐药…课件

1、Apatinib (YN968D1) reverses multidrug resistance by inhibiting the function of multiple ATP-binding cassette transporters Yanjun Mi, Liwu FuState Key Laboratory of oncology in southern China, Cancer Center, Sun Yat-sen University, Guangzhou, 510060, ChinaEmail: FBackgroundA successful cancer chemoth

2、erapy is limited by multidrug resistance (MDR). The major inducers of MDR are the ABC transporters, such as ABCB1 (anthracyclins, vinca alkaloids, taxanes, and epipodophyllotoxins), ABCG2 (mitoxantrone, anthracyclins, topoisomerase I inhbitors, methotrexate).Combination of modulator with conventiona

3、l chemotherapeutic drugs to restore the sensitivity of MDR cells is a main strategy for overcoming MDR.Tyrosine kinase inhibitors (TKIs) belong to a new class of anticancer drugs.TKIs including lapatinib, erlotinib and sunitinib, have been shown to overcome ABC transporters-mediated MDR in cancer ce

4、lls.Apatinib (YN968D1) is an oral small-molecule TKI that targets VEGFR-2, RET, c-Kit and c-Src tyrosine kinases. It is conceivable that apatinib may inhibit functions of ABC transporters by binding to their ATP-binding sites.BackgroundCytotoxicity of apatinib alone in all experimental cell linesMor

5、e than 85% of cells were viable at concentrations of apatinib up to 3.0 M in all experimental cells.ABCB1ABCB1ABCG2Apatinib reversed MDR in vitroCompoundsIC50 SD (M) (fold-reversal)S1S1-M1-80 (ABCG2)Mitoxantrone0.194 0.027(1.00)13.651 0.922(1.00)+ 0.75 M Apatinib0.196 0.041(0.98)6.434 0.478*(2.12)+

6、1.5 M Apatinib0.185 0.058(1.05)2.070 0.621*(6.59)+ 3.0 M Apatinib0.136 0.067(1.42)1.188 0. 495*(11.5)+ 2.5 M FTC0.188 0.011(1.03)0.892 0.056*(15.3)Topotecan0.262 0.042(1.00)10.281 0.455(1.00)+ 0.75 M Apatinib0.264 0.022(0.99)4.089 0.026*(2.51)+ 1.5 M Apatinib0.247 0.017(1.05)2.037 0.083*(5.04)+ 3.0

7、M Apatinib0.196 0.055(1.33)1.188 0.055*(8.65)+ 2.5 M FTC0.254 0.016(1.02)0.745 0.068*(13.8)Cisplatin12.811 1.181(1.00)12.092 1.322(1.00)+ 3.0 M Apatinib12.280 1.990(1.04)12.143 1.452(1.00)HL60HL60/ADR(ABCC1)Doxorubicin 0.036 0.002(1.00)5.704 0.378(1.00)+ 0.75 M Apatinib 0.035 0.002(1.04)5.493 0.289(

8、1.03)+ 1.5 M Apatinib 0.037 0.002(0.97)5.528 0.515(1.02)+ 3.0 M Apatinib 0.033 0.004(1.09)5.719 0.595(1.00)Apatinib reversed MDR in vitroCompounds IC50 SD (M) (fold-reversal)HEK293/pcDNA3.1HEK293/ABCG2-R2HEK293/ABCB1 Mitoxantrone 0.0569 0.0035(1.00) 1.3460 0.3143(1.00) 0.1381 0.0274(1.00) + 3 M Apat

9、inib 0.0349 0.0097(1.63) 0.0655 0.0199*(20.55) 0.0616 0.0357*(2.24) + 3 M FTC 0.0528 0.0093(0.98) 0.0687 0.0126*(19.59)- + 3 M PSC833 0.0543 0.0069(1.04)- 0.0688 0.0459*(2.01) SN-38 0.0073 0.0003(1.00) 0.1530 0.1636(1.00)- + 3 M Apatinib 0.0045 0.0009(1.62) 0.0079 0.0021*(19.37)- + 3 M FTC 0.0050 0.

10、0003(1.46) 0.0085 0.0016*(18.00)- Vincristine 0.0437 0.0022(1.00- 0.6405 0.0349(1.00) + 3 M Apatinib 0.0335 0.0039(1.30)- 0.1792 0.0485*(3.57) + 10 M Verapamil 0.0450 0.0003(0.97)- 0.0514 0.0025*(12.46) Doxorubicin 0.0724 0.0054(1.00)- 1.0821 0.5424(1.00) + 3 M Apatinib 0.0512 0.0033(1.41)- 0.3168 0

11、.0045*(3.42) + 10 M Verapamil 0.0957 0.0142(0.77)- 0.0964 0.0153*(11.23) Cisplatin 1.8240 0.4728(1.00) 1.6521 0.3892(1.00) 1.4899 0.5321(1.00) + 3 M Apatinib 1.5256 0.3717(1.19) 1.4193 0.4820(1.16) 1.6479 0.2402(0.90) Effect of apatinib on the accumulation of doxorubicin Effect of apatinib on the ac

12、cumulation of rhodamine 123ApatinibExpression of ABCB1 and ABCG2ABCB1 and ABCG2 ATPase activityReverse ABCB1- and ABCG2-mediated MDR Intracellular accumulation of drugs in the MDR cells Effect of apatinib on the expression of ABCB1 and ABCG2Effect of apatinib on the expression of ABCB1 and ABCG2Effe

13、ct of apatinib on ABCB1 and ABCG2 ATPase activity950nmol/L10-12nmol/LEffect of apatinib on the phosphorylation of AKT and ERK1/2 ApatinibABCB1 and ABCG2 ATPase activityExpression of ABCB1 and ABCG2MDRIntracellular accumulation of drugs in the MDR cells ReverseBlockade of AKT and ERK1/2 activation AcknowledgmentsWe like to thank Professor Su